Proteases are involved in diverse processes, such as blood coagulation, the cell cycle, infection and neurodegenerative disorders (Turk et al., Nat. Rev. Drug Discov. 2006, 5, 785-799; López-Otín et al., J. Biol. Chem. 2008, 283, 30433-30437). They are therefore attractive drug targets. However, non-selective inhibition of proteases can caused serious side effects. For example, non-selective inhibition of metalloproteases is thought to be the reason for musculoskeletal side effects seen in early matrix metalloprotease (MMP) inhibitors that were evaluated for cancer treatment (Coussens et al., Science 2002, 295, 2387-2392).
Modified peptides have potential for use as protease inhibitors. Efforts have been made to search for protease inhibitors amongst natural products produced by marine cyanobacteria (see Matthew et al., J. Nat. Prod. 2007, 70, 124-127; and Taori et al., J. Nat. Prod. 2007, 70, 1593-1600). This group of organisms is known to produce a vast array of secondary metabolites, among which there are lipophilic modified peptides that possess potent cytotoxicity (Luesch et al., J. Am. Chem. Soc. 2001, 123, 5418-5423; Taori et al., J. Am. Chem. Soc. 2008, 130, 1806-1807).
In recent years, with new developments in the areas of separation science, spectroscopic techniques, and microplate-based ultrasensitive in vitro assays, there has been a remarkable resurgence of interest in natural product research, for example, to find novel natural products that can be used as selective protease inhibitors.